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Advances in Cardiovascular Therapeutics: From the Bench to Clinical Outcome Trials

Effects of the Renin-Angiotensin System and Its Blockade in Blood Pressure Regulation and the Cardiovascular System

The renin-angiotensin system (RAS) is a potent biologic system, responsible for blood pressure control and body volume homeostasis, as well as a number of other physiologic and potential pathophysiologic actions (Table 1), according to Thomas Unger, MD, Director, Institute of Pharmacology and Toxicology, Charite Hospital, and Professor of Medicine, Humboldt University, Berlin, Germany. “The role of the RAS is three-fold: salt conservation, blood volume conservation, and blood pressure conservation. The inadequacy of any of its regulatory systems can lead to pathophysiologic effects, such as hypertension, endothelial dysfunction, and atherosclerosis,” Dr. Unger said. Inhibition of the RAS offers an important target not only for hypertension, but also for protection of related organs, such as the vasculature, heart, brain, and kidneys.

Pathophysiology of the RAS
The RAS is involved in a number of physiologic and pathophysiologic actions, related to the vascular, cardiac, and renal growth processes, which can affect vascular hypertrophy, cardiac remodeling, or renal fibrosis. Many of the RAS classical physiologic and pathophysiologic actions occur via the AT1 receptor. Angiotensin effects of vasoconstriction and atherosclerosis of the blood vessel, left ventricular hypotrophy and arrhythmia of the heart, salt and water retention, glomerulosclerosis of the kidney, stroke, and dementia can be mediated via the AT1 receptor. Angiotensin, for example, plays a role in the progression from endothelial dysfunction to atherosclerosis. “In addition, angiotensin, via the AT1 receptor, has been demonstrated to induce inflammatory and metabolic responses that can contribute to pathologic vascular, cardiac, and renal processes, leading to acute and chronic cardiovascular and metabolic events and diseases, such as myocardial infarction, stroke, heart failure, and renal insufficiency,” Dr. Unger said (Kaschina & Unger, Blood Pressure 2003).

Role of AT1 and AT2 Receptors
In many ways, the angiotensin AT2 and AT1 receptors act in opposition. “The AT2 is difficult to observe during normal conditions. However, in cases of stroke, renal failure, or vascular injury, such as myocardial infarction or heart failure, the AT2 receptor can be dramatically upregulated,” Dr. Unger explained. Actions of the AT2 receptor differ greatly from those of the AT1 receptor (Table 2).

In one animal study, the use of ramipril showed dose-dependent production of cyclic GMP, with the blockade of the bradykinin B2 receptor abolishing this effect. Treatment with losartan resulted in a much greater generation of cyclic GMP, despite identical effects on blood pressure and hemodynamics in the two groups. In another study, blockade of the AT2 receptor resulted in a halt to cyclic G and NO production, with an increase of cyclic GMP in the aorta, with vessel protective, anti-atherosclerotic, and vasodilatory actions (Gohlke et al, Hypertension 1996; Gohlke et al, Hypertension 1998).

“Thus, with blockade of the RAS via an angiotensin-converting enzyme [ACE] inhibitor, AT1 receptor antagonist, or both, different therapeutic effects may be achieved,” said Dr. Unger. Dr. Unger emphasized that further investigation is needed in this promising area of research, comparing single versus dual RAS blockade. “The ongoing ONTARGET study will compare use of the ACE inhibitor ramipril, versus the AT1 antagonist telmisartan, versus a combination of the two therapies in patients at high risk for cardiovascular events,” he said.


Interfacing the Circadian Variation of Blood Pressure and Cardiovascular Events

Recent data indicate that a 24-hour blood pressure measurement provides enhanced prediction of cardiovascular risk over use of office blood pressure measurements alone. “Patients who have white-coat hypertension but a < 130/80 mm Hg 24-hour blood pressure measurement have been shown to be at low risk for cardiovascular events,” said William B. White, MD, FACP, Professor of Medicine, Chief, Section of Hypertension and Clinical Pharmacology, University of Connecticut School of Medicine; and Director, Clinical Trials Unit, University of Connecticut Health Center, in Farmington, Connecticut. According to Dr. White, 24-hour blood pressure measurements also provide the best correlation with treatment effects on target organ damage, with new data showing that early-morning blood pressure surge is an independent predictor of events such as stroke and ischemic stroke.

Office versus 24-Hour Blood Pressure
According to Dr. White, research has clearly demonstrated the correlation between 24-hour blood pressure measurements and cardiovascular risk (Table 1). Verdecchia and colleagues, for example, found that ambulatory blood pressure measurements (ABPM) of < 136/87 in men and < 131/86 in women showed no increased risk for cardiovascular events over patients with normal office blood pressure (Hypertension 1994). As part of the recent Syst-Eur trial, Fagard and colleagues found that persons with non-sustained hypertension were at a lower risk for poor cardiovascular outcome than those with sustained hypertension. Active treatment of hypertension resulted in reduced cardiovascular events in patients with moderately sustained but not with non-sustained hypertension (Circulation 2000). Similarly, Clement and colleagues recently found ABPM to have significantly better predictability than office blood pressure measurements (OBPM) for cardiovascular events in hypertensive patients (N Engl J Med 2003). “The data indicate that 24-hour blood pressure measure provides more decision-making information to the physician, and is a better predictor than OBPM for cardiovascular risk and for anti-hypertensive treatment efficacy,” Dr. White explained.

Timing: Circadian Blood Pressure Fluctuations
It is well known that circadian rhythms can cause blood pressure to fluctuate throughout the day and night hours. Several recent studies point to the clinical implications of this phenomenon. As part of the Syst-Eur trial, Staessen and colleagues found not only that ABPM was a better predictor than OBPM of cardiovascular risk, but also that patients with high nocturnal blood pressure had increased cardiovascular event rates. Indeed, night-to-day ratio and 24-hour systolic blood pressure were shown to be independent predictors of cardiovascular endpoints (JAMA 1999).

In addition, certain times of the day—particularly the early morning—can be associated with a surge in blood pressure and correlated cardiovascular complications (Table 2). “The typical profile of the hypertensive patient involves a rise in blood pressure from the point of awakening to 4 or 5 hours later,” Dr. White noted. Kario and associates found that patients who experienced early-morning blood pressure surge had a higher prevalence of cardiovascular events than patients in the non-surge group. Specifically, silent infarction was 70% versus 48%, multiple ischemic infarction 57% versus 33%, and ischemic stroke 19% versus 7.3%, respectively, in the surge and non-surge groups.

Treatment Strategies
Circadian blood pressure fluctuations may be attributed to a number of factors, including variability of catecholamine levels, heart rate, and renin-angiotensin system (RAS) action. “Therefore, avoidance of early-morning angiotensin II excess may be an effective strategy to mitigate early-morning blood pressure surge in hypertensive patients,” Dr. White explained. In one multicenter randomized single-blind MICADO II trial, White and colleagues used baseline and treatment ABPM to measure the effects of treatment of hypertension with a long-acting angiotensin receptor blocker (ARB), telmisartan (40 mg) versus an intermediate-acting ARB, valsartan (80 mg). After 2 weeks, doses were titrated to telmisartan 80 mg or valsartan 160 mg. “After 2 months of therapy, ABPM results showed significantly greater reduction in the early morning BP in the telmisartan group compared to the valsartan group,” Dr. White said (Am Soc Hypertension 2003). Similarly, Lacourciere and colleagues randomized hypertensive patients to receive either telmisartan, amlodipine, or placebo. These data showed a significantly greater reduction in blood pressure during both sleep and early-morning hours in the telmisartan group (Blood Pressure Monitor 1998). “Increasingly, we are seeing data that indicate RAS modulation of early-morning blood pressure can be influenced by medical therapies that are pharmacodynamically active at that point in time,” Dr. White summarized.

“It is hoped that use of these and other new therapeutic options will allow for optimal management of blood pressure—particularly in the early-morning hours—and prevention of related cardiovascular events in hypertensive patients,” Dr. White noted.

Angiotensin II: Role in Vascular and Metabolic Complications of the Metabolic Syndrome

Angiotensin II plays a role not only in the pathophysiology of atherosclerosis, but also in the metabolic syndrome, said Arya M. Sharma, MD, FRCPC, Canada Research Chair for Cardiovascular Obesity Research and Management, and Professor of Medicine, McMaster University Department of Medicine, Hamilton, Ontario, Canada. “Blockade of the renin-angiotensin system [RAS] has been shown to reduce the risk of diabetes type II. In addition, angiotensin II may inhibit adipogenic differentiation of preadipocytes, with RAS angiotensin blockade leading to the formation of new fat cells and thus the reversal of ectopic lipid storage,” Dr. Sharma said. These findings hold promise for new treatment options that may help manage hypertension and the related metabolic syndrome.

Metabolic Syndrome and Cardiovascular Risk
Metabolic syndrome is associated with a number of characteristics, including abdominal obesity, low HDL cholesterol, and elevated triglycerides, blood pressure, and fasting glucose levels. Visceral obesity may lead to hypertension, but can also be a risk factor for left ventricular hypertrophy and congestive heart failure and serve as a key contributor to the development of impaired glucose tolerance, diabetes type II, and other pathophysiologic processes. In addition, Engeli and colleagues showed a relationship between inflammatory cytokines and obesity in post-menopausal women, with an increase in CRP levels in overweight and obese women compared with lean women. “These results suggest the need to consider the role of adipose tissue as a biologically important organ, contributing to vascular inflammation,” Dr. Sharma said.

The RAS Role in Metabolic Syndrome
Angiotensin II plays a key role in a number of the pathologic processes leading to atherosclerotic lesions. Angiotensin II is actively involved in cellular signals and autocrine factors that determine smooth muscle growth. In turn, this action is a key factor in producing pro-inflammatory processes that are found with atherosclerotic plaque, ultimately leading to inflammation, plaque rupture, and ischemic disease (Gibbons et al, Clin Cardiol 1997). “The pharmacologic blocking of the RAS is a powerful tool for interrupting and slowing this process to ischemic disease,” Dr. Sharma said.

In the MICRO-HOPE study, data from diabetic patients treated with either ramipril or placebo showed a dramatic benefit with the angiotensin- converting enzyme (ACE) inhibitor on all outcomes: total mortality, cardiovascular death, myocardial infarction, stroke, revascularization, and overt nephropathy (Hope Study, Lancet 2000).

In another study, Lewis and colleagues treated diabetic patients with irbesartan, amlodipine, or placebo. While blood pressure levels were similar between the treatment groups, a significant benefit was shown in the irbesatran arm in the primary endpoints of doubling time of serum creatinine, endstage renal disease, and death (N Engl J Med 2001).

In the LIFE study, diabetic patients were randomized to receive either atenolol or losartan. A significant reduction in mortality was observed in those taking the RAS blocker (Lindholm et al Lancet 2002).

Nakao and colleagues randomized diabetic patients to receive losartan, trandolapril, or a combination of the two. The combination therapy showed a significantly greater benefit in reaching the renal endpoint than either drug alone (Lancet 2003). “These findings suggest a clinical benefit of total RAS blockade, using a combination therapeutic approach,” said Dr. Sharma.

RAS Blockade and Diabetes
Interestingly, both the LIFE and HOPE studies showed a significant benefit in reducing new onset of diabetes II in patients receiving RAS-blocking agents. “Research has shown an abundance of AT1 receptors in adipose tissue, with in vitro studies clearly showing that adipocyte release of angiotensin II leads to inhibition of new fat cell formation,” Dr. Sharma explained (Sharma et al, Hypertension 2002).

Dr. Sharma and other investigators are now studying whether failure of adipocyte differentiation is a cause of diabetes type II. “The current hypothesis is that RAS blockade may allow for increased adipose site differentiation and increased formation of small insulin-sensitive adipocytes, thereby redirecting the flux of excess lipids back to adipose tissue. This, in turn, may lead to a reduction in myocytic lipid storage and perhaps improvements in insulin sensitivity,” Dr. Sharma explained. It is hoped that the upcoming ONTARGET trial will shed light on this issue, and show whether the beneficial metabolic effect of angiotensin blockade could be reversal of ectopic lipid storage.


Clinical Trials of ACE Inhibitors and A2 Receptor Blockade in Hypertensive Patients with Cardiovascular Comorbidity

Recent years have produced numerous studies focusing on the treatment of hypertension. “Data show that reducing blood pressure is effective in preventing cardiovascular events, both stroke and heart attack. More recent research has focused not only on the risk associated with blood pressure, but the overall cardiovascular risk of the patient,” said Stephen G. Ball, MB, PhD, Professor of Cardiology, British Heart Foundation, and Head, Academic Unit of Cardiovascular Medicine, University of Leeds, Leeds, United Kingdom. Dr. Ball provided an overview of the findings and implications of recent antihypertensive trials.

The Antihypertensive Data
In the HOPE study, high-risk hypertensive patients were randomized to receive ramipril or placebo in addition to usual therapy. The placebo cohort was at a 4% risk for stroke, heart attack, or death. Despite only a small difference in blood pressure between the two arms, cardiovascular risk was significantly lower in the ramipril group (HOPE study, N Engl J Med 2000; Lancet 2000). “These findings raise the question of whether the benefit observed was explained by the additional blood pressure reduction or another effect of renin-angiotension system [RAS] blockade,” Dr. Ball noted.

In the LIFE study, high-risk hypertensive patients were randomized to receive either atenolol or losartan. Despite identical blood pressure measurements in the two groups, losartan was associated with a significant reduction in risk of cardiovascular events, particularly stroke. This benefit was especially marked in the diabetic subpopulation (Dahlof et al, Lancet 2002). “In addition, both HOPE and LIFE studies appeared to show prevention of new-onset diabetes with RAS blockade,” Dr. Ball said.

In the ALLHAT study, patients were randomized to initial treatment with amlodipine, chlorthalidone, or lisinopril. Patients had stage I/II hypertension and one added risk factor. Similar results were shown with all three agents in terms of myocardial infarction and death from coronary heart disease. The systolic blood pressure with chlorthalidone was consistently lower than with the other two agents. The lisinopril group had a significantly increased rate of stroke, and overall, there was no added benefit observed for diabetic patients in this study (ALLHAT study, JAMA 2002).

In the open-trial Australian National Blood Pressure Study II, hypertensive patients received an angiotensin-converting enzyme (ACE) inhibitor or diuretic. Blood pressure reduction was similar in the two groups. The ACE inhibitor proved more effective in reducing the risk of death and all cardiovascular events, one of two primary endpoints (Wing et al, N Engl J Med 2003). This study was problematic in that it showed no such clinical benefit in women and non-cardiovascular death featured prominently in the overall difference in outcome. “These data emphasize that adequate blood pressure is key to reducing a patient’s cardiovascular risk—and, for many patients, this may require a combination of two or three different antihypertensive agents,” Dr. Ball explained.

Future Directions
Further research is needed to define the full effect of RAS blockade. “The research shows that reducing blood pressure is effective in reducing cardiovas- cular risk, irrespective of the origin of that risk, but also suggests that a small additional benefit may be gained from RAS blockade,” Dr. Ball said. The results of upcoming studies, such as the ONTARGET trial—comparing an ACE inhibitor, angiotensin receptor blocker, and combination therapy—will provide further insight into the role of blockade of the RAS in therapy.

 

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